Although combination antiretroviral therapy (ART) has been successful in suppressing plasma HIV RNA levels in infected patients, it has not resulted in eradication of virus. It is now clear that prolonged, continuous ART results in significant toxicities and adherence to drug regimens is difficult. In addition, the cost of HAART drugs is prohibitive for many countries and individuals. Therefore, we have studied the virologic and immunologic effects of intermittent versus continuous ART in HIV-infected individuals in an attempt to reduce the total time an individual received therapy while maintaining therapeutic efficacy. Ongoing studies include a randomized, controlled trial of long cycle intermittent ART (1 month off ART followed by 2 months on ART for 22months), pilot studies of short cycle intermittent ART (7 days off ART followed by 7 days on ART for up to 52 months) and randomized, controlled trials in the U.S. and Uganda of short cycle intermittent versus continuous ART for the treatment of chronic HIV infection. Following 4-7 cycles of long cycle intermittent therapy, 19 of 22 patients had detectable plasma viremia after each of the 1 month off-drug periods. There was no significant difference in the mean plasma HIV RNA level between the 1st and the 4th cycles off drugs. However, all patients had a viral load of < 500 copies/ml following each of the 2 months on-drug periods; 70% of patients had plasma HIV RNA of < 50 copies/ml after the on-ART periods. A comprehensive evaluation of this patient cohort demonstrated a lack of clear therapeutic benefit in terms of virologic and immunologic effects, as well as of multiple parameters of toxicity, in individuals who received at least 48 weeks of long-cycle intermittent therapy. More importantly, efavirenz, and other non-nucleoside reverse transcriptase inhibitors cannot be recommended for use in long cycle intermittent ART strategies due to the increased risk of developing resistance to these agents. In a previous study, we demonstrated that patients receiving short cycle intermittent therapy (7 days on ART with a dual protease inhibitor-based, twice per day regimen followed by 7 days off) maintained suppression of plasma HIV viremia while reducing serum lipid levels. However, adherence to a twice-a-day regimen is difficult. Thus, we investigated a proof-of concept study consisting of short cycle intermittent ART with once per day regimen of didanosine, lamivudine and efavirenz in chronically infected patients. Seven of 8 patients evaluated maintained suppression of plasma HIV RNA for 60-84 weeks (30-42 cycles) while preserving CD4+ T cell counts. In addition, there was no evidence for the emergence of drug resistance to antiretroviral drugs. We are currently evaluating whether viral evolution occurs in these patients despite levels of plasma viremia below the limit of detection. Our goal in this study is to assess the effect of short-cycle antiretroviral therapy versus continuous ART at the genetic level of the virus in order to further demonstrate the safety and efficacy of short-cycle therapy. It is important to note that the need for strict adherence to a short-cycle intermittent ART regimen is necessary and the feasibility of this approach will require randomized, controlled clinical trials. In this regard, we are conducting a randomized, controlled trial of two short cycle intermittent therapy approaches versus continuous ART in Kampala, Uganda. In summary, short cycle intermittent ART may offer new hope for the treatment of HIV infection by reducing cost and possibly toxicities while potentially enhancing adherence. If safety and efficacy of short-cycle intermittent therapy is ultimately demonstrated in clinical settings, it might prove to be an important strategy to expand therapy in resource-limited settings.